Hansell Stedman, a surgeon who had two brothers with Duchenne muscular dystrophy, aims to translate lessons from crush injuries into improvements in gene therapy
You don’t have to look far to figure out how Hansell Stedman got interested in Duchenne muscular dystrophy (DMD). His older brother, Holt, and younger brother, Roland, had the disease.
Holt would die at the age of 23 in 1978, and Roland the same year, at 19. But two years earlier, when the family was living in Atlanta, Roland won an award for a high school science project about mice that had an inherited muscular dystrophy. Back then, none of the muscular dystrophy genes had been identified. (Many years later, these mice were found to have mutations that cause a deficiency of the laminin 211 protein and to develop a disease mimicking merosin-deficient congenital MD.)
In the summer of 1976, Hansell came home to Atlanta after finishing his first year at the Massachusetts Institute of Technology, where he had been planning to major in physics or chemistry. Roland told him about the mice and about his biology studies. “I was captivated by what my younger brother was telling me, and my older brother was echoing, about biology,” Stedman says. “They were talking about breeding these mice and genes and chromosomes, and I thought it was time for me to broaden my horizons and take a good biology course.”
Back at MIT that fall, Stedman’s entry-level biology course “absolutely captivated” him. “It was a philosophical leap, the idea that we can look inside our own bodies with the tools of genetics and dissect how they work and why they don’t work”, he says. “The prospect of understanding biology at a level of detail that one would need to do anything about a genetic disease was daunting and fascinating. I figured if my own brothers were able to see past the daunting side of this into the fascinating side, I could roll up my sleeves and pick up the challenge." He switched his major to biology and chemistry, graduating in 1979.
Stedman would go on to Harvard Medical School, concentrating in genetics and completing his degree in medicine in 1983. Later, at the University of Pennsylvania, he would become a surgeon. But he interrupted his surgery training for MDA-funded postdoctoral studies in human genetics and in cell and developmental biology along the way.
In the late 1980s, just as Stedman's career was beginning, mutations in the gene for the muscle protein dystrophin were identified as the underlying cause of DMD. Those that result in a complete lack of dystrophin protein in muscle fibers were found to cause DMD, while those resulting in a partial lack of the protein were found to result in the less severe Becker muscular dystrophy (BMD).
Stedman couldn’t have anticipated it in those early days, but his combined interests in muscle biology, genetics and surgery would prove to be an ideal combination for working on dystrophin deficiency.
By the 1990s, physicians and biologists, Stedman included, were talking about gene-transfer therapy — injecting therapeutic genes — as a possible way to treat DMD and other diseases.
The challenge of the immune system
It would soon become clear that one formidable obstacle to treating a genetic disease with gene therapy is the body’s own immune system, which is likely to see proteins made from new genes as potentially threatening, especially if the new genes are delivered inside viruses — which turns out to be the most efficient way to get lots of genes into tissues.
For DMD, gene transfer is particularly daunting, because the dystrophin gene is so large that it has to be miniaturized to make it fit inside a delivery system.
It wasn’t entirely a surprise to Stedman when, in 2010, a small trial of dystrophin gene-transfer therapy in boys with DMD showed that the immune system had apparently posed a barrier to the effectiveness of the treatment.
A lesson from crush injuries
In thinking about the 2010 trial, Stedman was reminded of a frequent and baffling problem facing doctors treating patients with severe crush injuries. They would often develop a condition resembling sepsis — whole-body inflammation. Sepsis is normally associated with overwhelming infection, but surgeons treating seriously injured patients would sometimes see it even when no infection could be found.
A leading explanation for sepsis occurring in uninfected wounds from crush injuries is that cellular structures called mitochondria, which produce energy and are plentiful in muscle fibers, are damaged during crush injuries. Mitochondria, it seems, resemble bacteria, and they alert the immune system in the same way that a bacterial infection would.
“The intriguing theory about why these patients with crush injury look like they’re in sepsis is that part of mitochondria spill out of damaged muscle cells and trigger rapid, innate immune responses designed to ward off infections,” Stedman says. “It’s the enemy from within.”
In DMD and other muscular dystrophies, Stedman says, there are “tiny versions of crush injury” going on all the time in the musculature, as muscle fibers degenerate. That creates a constant “inflammatory” environment, he believes, with the immune system on high alert at all times. When presented with a seemingly foreign protein or something that looks like a virus, it mounts an all-out attack, killing what it sees as “infected” cells.
Icebergs right and left
Stedman compares this immune defense of muscle fibers to the way the Titanic was designed. Small and occasional damage to a muscle fiber attracts the immune system, which brings in inflammatory cells while the muscle walls off the damaged area until it can be repaired or scarred over. Meanwhile, the rest of the muscle continues to function.
The Titanic was designed so that individual compartments could be sealed off for later repair, while the ship remained afloat, but its architects never envisioned an iceberg of the type that ripped through several of these compartments at once, causing the ship to sink.
In DMD-affected muscle fibers, he says, the lack of dystrophin is like “icebergs right and left,” ultimately overwhelming the muscle fiber’s ability to seal off the damage.
Stedman says he’s “fascinated by the details of this process” and thinks there will be ways in which an improved understanding should help us design ways to protect cells from it.
Dealing with inflammation
A current MDA grant to Stedman will help his team explore the inflammatory environment in DMD and figure out how to outwit it so that gene therapy can be more effective. “We want to understand at a fundamental level the earliest events that take place, how the innate immune system draws a set of cells into play to rapidly clear out debris and set the stage for the repair process,” he says. “We want to leverage that knowledge to come up with the most specific possible ways to deal with the inflammatory state of muscle while we’re launching a gene therapy to try to treat it.”
He and his colleagues are now studying dogs that make no dystrophin and are closer in size and physiology to humans than mice are.
For now, Stedman is pursuing gene transfer therapy in dystrophin-deficient dogs using a miniaturized gene for utrophin — a protein that appears to be able to stand in for dystrophin but which is likely to be better tolerated by the immune system, because dystrophin-deficient dogs (and people) make utrophin from birth.
“The goal is to come in and pinch-hit for dystrophin without triggering an immune response,” Stedman says of his current gene-transfer efforts. “We want to transfer a miniaturized utrophin gene that has been engineered to make as much utrophin as it possibly can and to fly it below the immune system’s radar so we can safely deliver it to every muscle cell in the body, including the heart.”
He remains optimistic about gene therapy for DMD and other muscular dystrophies. “We’re doing our level best to try to address what we think are the most important questions related to the most challenging bottlenecks, as we gear up to move forward into rational and appropriate clinical trials.”
Want To Know More?
This article is part of a special series titled Gene Therapy: The Next Generation, which includes these additional articles profiling researchers who are pursuing next-generation gene therapy for DMD:
For more information about Stedman's gene transfer research, be sure to read: